Jim Wells: Helping to Fill the Drug Discovery Pipeline

Jim Wells

Cancer, diabetes, inflammation, malaria. The list of diseases ripe for new treatments is long. Yet the pace of drugs coming to market is actually flat. A key reason is the drug discovery process itself, says Jim Wells, director of the Small Molecule Discovery Center (SMDC) at the California Institute for Quantitative Biomedical Research, or QB3, at UCSF's Mission Bay campus. It takes about $1 billion and 10 years to discover, develop and get approval for a new drug, Wells says. The high failure rate all along the discovery and development pathway has prompted pharmaceutical companies to focus on the relatively few proteins in the body that can be targeted by blockbuster drugs to treat the most common ailments - drugs that can generate millions of prescriptions and hundreds of millions of dollars in sales a year. Think cholesterol-busting statins and pills for allergies, sleeping or erectile dysfunction. Drug Discovery That leaves a pretty dry pipeline of new drugs to treat many of the world's most devastating diseases. One way to get more new compounds all the way from the laboratory to the medicine cabinet is refining the screening process. Here's how it normally works: Once researchers identify an enzyme or other protein essential to the normal progress of a disease, a search can begin for potential, new drugs to inhibit the enzyme's action. The standard strategy, called high-throughput screening (HTS), is an automated process in which hundreds of thousands, even millions, of small compounds are tested at pharmaceutical companies for their ability to disrupt the normal functioning of a protein. A successful compound chemically binds to a key site in the enzyme, blocking the enzyme's access to its normal binding partner and thereby interrupting the signal that would trigger the disease to advance. The largest pharmaceutical market in the world, for example, is for statins, which inhibit a key cholesterol-producing enzyme in the body. The compounds are referred to as small molecules, since they are often about one-hundredth the size of the target protein. High-throughput screening is an intelligent shotgun approach, and few compounds are expected to succeed. But if enough are screened, some will be "hits" - potential drugs against a target protein. Still, many targets receive no hits, and are deemed "undruggable," Wells explains.

Jim Wells, director of the Small Molecule Discovery Center at the California Institute for Quantitative Biomedical Research, or QB3, talks about his work to members of the Forum of Young Global Leaders, including San Francisco Mayor Gavin Newsom.

As director of the SMDC, Wells heads an effort to screen novel targets and improve ways to identify promising drug candidates. The SMDC serves two roles, really. Scientists there, led by Associate Director Adam Renslo, carry out conventional HTS to help other UC investigators find novel small molecules that can disrupt protein targets involved in key biological processes. (A compound to kill the malaria parasite and another compound to block protein production in cancer cells are two current collaborations.) Scientists at the SMDC also pursue entirely novel ways to discover drugs, providing new directions for the pharmaceutical industry and even identifying promising compounds in the process. Tethering Pioneer Elected to the prestigious National Academy of Sciences in 1999, Wells joined the UCSF faculty, where he is the Harry W. and Diana V. Hind Distinguished Professor in Pharmaceutical Sciences, in 2005. He holds faculty positions in both the School of Pharmacy and the School of Medicine. He came to UCSF from a company he founded, called Sunesis Pharmaceuticals, where he pioneered a new and quite clever strategy called Tethering to more easily identify drug candidates, and even discover some that would otherwise never be recognized through conventional high-throughput screening. The Tethering process screens fragments, rather than entire compounds. Instead of screening, say, a million compounds in search of a drug to block cancer growth, a thousand fragments might be screened. Fragments bind much more weakly than the larger compounds discovered by HTS, and Tethering provides a sensitive means to identify fragments that HTS cannot find. After one promising fragment is identified, a second round of Tethering might discover another fragment. When the two fragments are linked, they can bind more strongly to the target and constitute the lead to a potential, new drug that HTS may miss. "With the larger molecule, you need a near-perfect fit to bind to the target protein," Wells explains. "But with the fragment-based approach, you only need part of it right to get the fragment to bind to the protein." Tethering also can pinpoint fragments for specific sites on the target protein, which HTS cannot do. Perhaps most important for drug discovery, the fragment-based strategy can discover compounds that work at previously unsuspected binding sites on the target protein. "Proteins usually interact with a handful of other proteins or molecules," Wells says. "Often, when the known active site of an enzyme fails to yield a drug-like compound, the target is abandoned. Tethering allows us to discover alternate sites on these targets, and enables us to continue the discovery process - to get another shot at the goal." In his own UCSF lab, Wells is advancing the fragment-based strategy to gain a deeper understanding of enzymes known as caspases - proteins critical to the normal processes of inflammation and cell death, or apoptosis - to aid in his search for compounds to hit alternative binding sites on these enzymes. Conventional efforts to block caspases have not worked. Wells has evidence that compounds able to target alternative binding sites might well inhibit caspases, leading to greater understanding of their critical natural roles and possibly opening the way for developing new drugs to reduce inflammation and redirect the cells' life-death decisions. "These are exciting times," Wells says. "The confluence of world-class biology with new approaches to chemical discovery will surely enrich the pool of potential drugs. That has to lead to novel, life-saving treatments." Photo/Sunesis

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